Autocrine Mfge8 Signaling Prevents Developmental Exhaustion of the Adult Neural Stem Cell Pool

• Published in: Cell stem cell Vol. 23; no. 3; pp. 444 - 452.e4
• Main Authors: Zhou, Yi, Bond, Allison M., Shade, Jamie E., Zhu, Yunhua, Davis, Chung-ha O., Wang, Xinyuan, Su, Yijing, Yoon, Ki-Jun, Phan, Alexander T., Chen, William J., Oh, Justin H., Marsh-Armstrong, Nicholas, Atabai, Kamran, Ming, Guo-li, Song, Hongjun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.09.2018
• Subjects: adult neural stem cells; hippocampus; Mfge8; mTOR; neurogenesis; PTEN; quiescence; RGL; adult neural stem cells; hippocampus; RGL; neurogenesis; mTOR; PTEN; quiescence; Mfge8
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2018.08.005

Adult neurogenesis, arising from quiescent radial-glia-like neural stem cells (RGLs), occurs throughout life in the dentate gyrus. How neural stem cells are maintained throughout development to sustain adult mammalian neurogenesis is not well understood. Here, we show that milk fat globule-epidermal growth factor (EGF) 8 (Mfge8), a known phagocytosis factor, is highly enriched in quiescent RGLs in the dentate gyrus. Mfge8-null mice exhibit decreased adult dentate neurogenesis, and furthermore, adult RGL-specific deletion of Mfge8 leads to RGL overactivation and depletion. Similarly, loss of Mfge8 promotes RGL activation in the early postnatal dentate gyrus, resulting in a decreased number of label-retaining RGLs in adulthood. Mechanistically, loss of Mfge8 elevates mTOR1 signaling in RGLs, inhibition of which by rapamycin returns RGLs to quiescence. Together, our study identifies a neural-stem-cell-enriched niche factor that maintains quiescence and prevents developmental exhaustion of neural stem cells to sustain continuous neurogenesis in the adult mammalian brain. [Display omitted] •Mfge8 is enriched in quiescent neural stem cells•Mfge8 deletion depletes neural stem cells and decreases adult neurogenesis•Mfge8 promotes early postnatal and adult neural stem cell quiescence•Mfge8 regulates neural stem cell quiescence via mTOR1 signaling Zhou et al. identify Mfge8, traditionally known for its role in phagocytosis, as a neural-stem-cell-enriched niche factor that maintains the neural stem cell pool in the dentate gyrus during early postnatal development and in adulthood by promoting neural stem cell quiescence.